非霍奇金淋巴瘤患者甲氨蝶呤血药浓度影响因素及毒副作用相关性研究

发布时间：2018-01-24 19:58

本文关键词： 非霍奇金淋巴瘤甲氨蝶呤血药浓度延迟排泄肌酐清除率　出处：《河北医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的:通过液相色谱串联质谱法(Liquid Chromatography Mass Spectrometry/Mass Spectrometry,LC-MS/MS)监测非霍奇金淋巴瘤((Non-hodgkin lymphoma,NHL)患者在应用大剂量甲氨蝶呤(High-dose methotrexate,HD-MTX)化疗后血药浓度,分析影响甲氨蝶呤(Methotrexate,MTX)血药浓度的因素。研究甲氨蝶呤血药浓度与其发生毒副反应之间的相关性,为临床实际工作中合理的应用甲氨蝶呤并制定正确的解救治疗方案提供依据。方法:对2016年1月至2016年12月期间38例于河北医科大学第四医院接受HD-MTX治疗的成人及儿童NHL患者进行血药浓度监测,共计60例次,均为甲氨蝶呤44小时血药浓度,其中男性38例次,女性22例次,年龄2岁至67岁。HD-MTX剂量为1-5g/m2,全部MTX药量24h持续静脉滴注。用药当日及其后3天内充分水化及碱化尿液,滴注甲氨蝶呤36 h后开始给予亚叶酸钙(Calcium Folinate,CF)进行解救。初始解救剂量为15 mg/m 2,每6 h静脉注射,具体解救剂量及次数根据甲氨蝶呤血药浓度进行调整。采用LC-MS/MS法测定HD-MTX用药后44h血清中MTX浓度,甲氨蝶呤浓度(C44 h)1.0μmol·L-1为排泄延迟组,甲氨蝶呤浓度(C44 h)≤1.0μmol·L-1为正常组,其中正常排泄组56例次,排泄延迟组4例次。1记录患者年龄、体重指数(Body mass index,BMI)值、MTX给药剂量,用独立样本t检验与多元线性回归分析患者性别、年龄、BMI值、MTX给药剂量与甲氨蝶呤浓度(C44 h)的相关性。2记录治疗后(44h)的血肌酐清除率(Creatinine clearance,Ccr),分析肌酐清除率(Ccr)与C44 h的相关性。3记录HD-MTX化疗后1-7天内发生的骨髓抑制、肝功能异常、肾功能异常、胃肠道反应、黏膜损害、皮疹、继发感染等甲氨蝶呤毒副反应。毒副反应分级依据NCI-CTC毒性标准分级分为Ⅰ度至Ⅳ度。比较MTX正常排泄组与延迟排泄组毒副反应发生率的相关性。结果:1单因素分析显示甲氨蝶呤浓度(C44 h)与患者年龄、MTX给药剂量、BMI值显著相关(P0.05),与患者性别不相关。多元线性回归分析显示患者年龄、MTX给药剂量是甲氨蝶呤浓度(C44 h)显著独立影响因素。2甲氨蝶呤浓度(C44 h)的排泄延迟率为6.67%,治疗后44 h肾功能正常组与肾功能受损组的甲氨蝶呤浓度(C44 h)对比,差异均有统计学意义(P0.05)。3甲氨蝶呤毒副反应发生率分别为骨髓抑制(68.3%)、胃肠道反应(40.0%)、继发感染(33.3%)、肝功能异常(33.3%)、黏膜损害(30.0%)、肾功能异常(20.0%)、皮疹(11.7%)。4延迟排泄组毒副反应发生率高于正常组,其中肾毒性差异显著(P0.05)而骨髓抑制、继发感染、胃肠道反应、肝功能异常、黏膜损害、皮疹的发生率两组间无明显差异(P0.05)。结论:1患者年龄、HD-MTX的给药剂量是影响甲氨蝶呤浓度(C44 h)的显著独立影响因素。2肾功能正常的患者44 h的Ccr与甲氨蝶呤浓度(C44 h)存在着明显相关性,提示肾功能仍是影响甲氨蝶呤排泄的主要因素之一。3甲氨蝶呤浓度(C44 h)监测可以有效的预判断MTX的排泄延迟,并为临床正确应用甲氨蝶呤以及制定亚叶酸钙解救方案提供合理的依据。
[Abstract]:Objective: by liquid chromatography tandem mass spectrometry (Liquid Chromatography Mass Spectrometry/Mass Spectrometry, LC-MS/MS) monitoring of non Hodgkin's lymphoma (Non-hodgkin (lymphoma, NHL) patients were treated with high dose methotrexate (High-dose methotrexate, HD-MTX) blood concentration after chemotherapy, analysis of the effect of methotrexate (Methotrexate, MTX) factors of blood concentration of methotrexate. The correlation between plasma concentration and adverse reaction, for reasonable clinical application of methotrexate in practical work and provide the basis for the formulation of the correct rescue treatment. Methods: blood concentration monitoring in 38 cases during the period from January 2016 to December 2016 in the fourth hospital of Hebei Medical University in HD-MTX treated adults and children with NHL, a total of 60 cases. For 44 hours the blood concentration of methotrexate, including male 38 cases, female 22 cases, aged 2 to 67 years old.HD The dose of -MTX 1-5g/m2, all 24h MTX dose continuous intravenous drip medication. Adequate hydration and alkalization of urine within 3 days of the day and after infusion of methotrexate after 36 h was given calcium folinate (Calcium Folinate, CF) were rescued. The initial rescue dose of 15 mg/m 2, each of the 6 h intravenous injection, specific rescue dose and times were adjusted according to blood concentration of methotrexate. Measured by LC-MS/MS HD-MTX after administration of 44h in the serum concentration of MTX, concentration of methotrexate (C44 h) 1 mol - L-1 elimination delay group, methotrexate (C44 h) less than or equal to 1 mu mol L-1 in the normal group, the normal group of 56 cases. In 4 cases, delayed excretion of group.1 patients were recorded age, body mass index (Body mass, index, BMI) value, MTX dosage, regression analysis of the sex of the patient, with the independent sample t test and multiple linear age, BMI value, MTX dosage and methotrexate concentration (C44 h) correlation.2 Recorded after treatment (44h) blood creatinine clearance rate (Creatinine, clearance, Ccr), analysis of creatinine clearance rate (Ccr) and the inhibition of C44 correlation between H.3 records 1-7 days after HD-MTX chemotherapy in bone marrow, liver dysfunction, renal dysfunction, gastrointestinal reaction, mucosa damage, skin rash, toxicity secondary infection of methotrexate toxicity grading classification. According to the NCI-CTC toxicity criteria were divided into four degree. The degree to rate correlation between MTX group and normal group delayed excretion excretion toxicity. Results: 1 single factor analysis showed that the concentration of methotrexate (C44 h) and the age of patients, MTX dosage, BMI value was significantly correlated (P0.05), not related with gender. Multiple linear regression analysis showed that age, MTX dose methotrexate (C44 h) is a significant independent factors affecting the.2 concentration of methotrexate (C44 h) the delayed excretion rate of 6.67%, 44 h after treatment of renal function Group of methotrexate with impaired renal function group (C44 h) comparison, the differences were statistically significant (P0.05).3 methotrexate toxicity was myelosuppression (68.3%), gastrointestinal reactions (40%), secondary infection (33.3%), abnormal liver function (33.3%), (30%), mucosal damage abnormal renal function (20%), rash (11.7%).4 delayed excretion group adverse reaction rate is higher than the normal group, the renal toxicity was significantly different (P0.05) and bone marrow suppression, secondary infection, gastrointestinal reactions, abnormal liver function, mucosal injury, the incidence of rashes was no significant difference between the two groups (P0.05). Conclusion: 1 patients age, the dosage is HD-MTX (C44 h) effects of methotrexate concentration significantly independent determinants of.2 patients with normal renal function 44 h Ccr (C44 h) and methotrexate concentration has significant correlation, suggesting that renal function is the principal factor influencing the excretion of methotrexate A.3 methotrexate concentration (C44 h) monitoring can effectively predict the excretion delay of MTX, and provide a reasonable basis for the correct application of methotrexate and the formulation of calcium folate rescue plan.

【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R969

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